A GREB1-steroid receptor feedforward mechanism governs differential GREB1 action in endometrial function and endometriosis

Authors: CHADCHAN, SANGAPPA - Baylor College Of Medicine; POPLI, POOJA - Baylor College Of Medicine; LIAO, ZIAN - Baylor College Of Medicine; ANDREAS, ERYK - Washington University School Of Medicine; DIAS, MICHELLE - Baylor College Of Medicine; WANG, TIANYUAN - National Institute Of Environmental Health Sciences (NIEHS, NIH); GUNDERSON, STEPHANIE - Washington University School Of Medicine; JIMENEZ, PATRICIA - Washington University School Of Medicine; LANZA, DENISE - Baylor College Of Medicine; LANZ, RAINER - Baylor College Of Medicine; FOULDS, CHARLES - Baylor College Of Medicine; MONSIVAIS, DIANA - Baylor College Of Medicine; DEMAYO, FRANCESCO - National Institute Of Environmental Health Sciences (NIEHS, NIH); YALAMANCHILI, HARI - Children'S Nutrition Research Center (CNRC); JUNGHEIM, EMILY - Washington University School Of Medicine; HEANEY, JASON - Baylor College Of Medicine; LYDON, JOHN - Baylor College Of Medicine; MOLEY, KELLE - Washington University School Of Medicine; O'MALLEY, BERT - Baylor College Of Medicine; KOMMAGANI, RAMAKRISHNA - Baylor College Of Medicine

Submitted to: Nature Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/16/2024
Publication Date: 3/2/2024
Citation: Chadchan, S.B., Popli, P., Liao, Z., Andreas, E., Dias, M., Wang, T., Gunderson, S.J., Jimenez, P.T., Lanza, D.G., Lanz, R.B., Foulds, C.E., Monsivais, D., Demayo, F.J., Yalamanchili, H.K., Jungheim, E.S., Heaney, J.D., Lydon, J.P., Moley, K.H., O'Malley, B.W., Kommagani, R. 2024. A GREB1-steroid receptor feedforward mechanism governs differential GREB1 action in endometrial function and endometriosis. Nature Communications. 15:Article 1947. https://doi.org/10.1038/s41467-024-46180-4.
DOI: https://doi.org/10.1038/s41467-024-46180-4

Interpretive Summary: GREB1 (Growth Regulation by Estrogen in Breast Cancer 1) is a critical mediator of steroid hormone receptor activity, with distinct roles in endometrial function and endometriosis. This research reveals that GREB1 acts through a feedforward mechanism with steroid receptors, specifically estrogen and progesterone, to regulate gene expression differently depending on the context. In healthy endometrial tissue, GREB1 facilitates progesterone action, enhancing the expression of genes necessary for normal endometrial function and receptivity. Conversely, in endometriosis, GREB1 is influenced by estrogen, which promotes the growth and maintenance of endometriotic lesions through estrogen-dependent gene expression. This differential regulation by GREB1 underscores its significant roles in both maintaining normal endometrial function and contributing to endometriosis pathology. Potential implications for pediatric nutrition research include exploring the role of GREB1 in metabolic pathways influenced by estrogen and progesterone, which are crucial during puberty and adolescence. Understanding how GREB1 interacts with these hormones could provide insights into managing metabolic disorders, where hormonal regulation plays a significant role.

Technical Abstract: Cellular responses to the steroid hormones, estrogen (E2), and progesterone (P4) are governed by their cognate receptor’s transcriptional output. However, the feed-forward mechanisms that shape cell-type-specific transcriptional fulcrums for steroid receptors are unidentified. Herein, we found that a common feed-forward mechanism between GREB1 and steroid receptors regulates the differential effect of GREB1 on steroid hormones in a physiological or pathological context. In physiological (receptive) endometrium, GREB1 controls P4-responses in uterine stroma, affecting endometrial receptivity and decidualization, while not affecting E2-mediated epithelial proliferation. Of mechanism, progesterone-induced GREB1 physically interacts with the progesterone receptor, acting as a cofactor in a positive feedback mechanism to regulate P4-responsive genes. Conversely, in endometrial pathology (endometriosis), E2-induced GREB1 modulates E2-dependent gene expression to promote the growth of endometriotic lesions in mice. This differential action of GREB1 exerted by a common feed-forward mechanism with steroid receptors advances our understanding of mechanisms that underlie cell- and tissue-specific steroid hormone actions.